Stimulants may be driving a "fourth wave" of the overdose crisis, with deaths at an all-time high

Earlier this week, Stephen Murray got a call on the Massachusetts Overdose Prevention Helpline, where responders stay on the phone with people using drugs in case they overdose so they can call emergency services. Murray asked the caller questions to try to gauge their responsiveness, but over the span of about 15 minutes, he lost the conversation and heard their breathing become short and infrequent on the line.

"It got to the point where I was like, 'Okay, I have to call now because I can't verify this is sustainable with life,'" Murray told Salon in a phone interview.

Murray, the Harm Reduction Program Manager at Boston Medical Center, has survived an overdose himself and is also a paramedic. He created the hotline in 2020 as a form of harm reduction. In 2023, it has fielded over 500 calls in the state and beyond, and Murray and his team have seen a growing number of people who identify as primarily or exclusively stimulant users, he said.

More than one million people have died from a drug overdose since 1999, with the number of deaths steadily increasing over the years. In the 12 month period ending in April 2022, more than 111,000 people experienced a fatal overdose, according to the latest provisional data from the Centers for Disease Control and Prevention. The crisis has become so pervasive that about the same number of Americans died from drug overdoses last year as they did from diabetes.

To describe this phenomenon, some drug policy experts have used a model of "waves." In the early 2000s, overdose deaths were driven primarily by prescription opioid use in the first "wave" of the crisis. As the drug supply was restricted over time, people who were already using opioids turned to other drugs instead. In 2010, the second wave saw more people using heroin, which was quickly followed by a third wave in 2013 driven by synthetic opioids like fentanyl, which were involved in two-thirds of overdose deaths in 2022. 

A new study confirms what many have suspected: We are now in the throes of the fourth wave of the overdose crisis, driven by multi-substance use — not just opioids, but stimulants as well. Writing in the journal Addiction, researchers found the portion of overdose deaths attributed to fentanyl and stimulants used together rose from 0.6% in 2010 to 32% in 2021, with that increase sharply rising in 2015.

While some studies have emphasized "signals of polysubstance overdose death can be traced back for decades," that signal seems to be getting much stronger. And although overdose deaths caused by prescription opioids and heroin in the first and second waves have decreased over time, these initial waves have not gone away either, emphasized study author Chelsea L. Shover, Ph.D., an assistant professor-in-residence at the University of California, Los Angeles.

"They are all still happening," Shover told Salon in a phone interview. "It's just that this is adding to an already pretty dire situation."

The reasons behind the rise in overdose deaths due to concurrent fentanyl and stimulant use are complex and not fully understood. In a Washington Post analysis published this week, the number of prescription hydrocodone and oxycodone pills decreased by 45% from 2011 to 2019, in part due to major litigation against opioid manufacturers and reduced prescribing patterns in the medical community. However, the number of overdose deaths due to prescription pills has stayed about the same.

"Ironically, the move to pull opioids from the shelves has made us less safe," Murray said. "Overdose rates have gone up from 20,000 a year to 100,000 a year and opioid prescribing is not a driver of this anymore."

Instead, the driver may be a rise in counterfeit or contaminated pills circulating in the drug supply, said Dr. Daniel Ciccarone, a substance use researcher at the University of California, San Francisco, who coined the term "fourth wave" in relation to the crisis. People who intend to take stimulants, for example, may unknowingly overdose on drugs laced with fentanyl or other synthetic drugs. 

There may also be intentional multi-drug use at play. Some who use stimulants take opioids or benzodiazepines to come down from a high, Murray said. Or vice versa: people who use fentanyl or opioids may use stimulants to combat some of their depressant effects, Shover added.

People have historically used drugs together with opioids for similar purposes, but fentanyl and other synthetic opioids are different. Because fentanyl can be both extremely potent and unpredictable in its potency, it may be causing overdose deaths in people who identify as primarily stimulant users, have a relatively low opioid tolerance and unknowingly take fentanyl, Murray said. That also influences harm reduction because people using primarily stimulants might not be prepared with naloxone or other life-saving materials when they are using drugs.

"If you have no opiate tolerance and you've been using stimulants for four or five days and then you sniff a little bit of a fentanyl to come down, your autopsy is going to show both the stimulants in your system and the fentanyl in your system," Murray said. "It's probably the fentanyl that killed you, but that person would not have been identified as someone who was at risk for [opioid] overdose because they were not someone who regularly used opioids, nor would they have said that in an interview."

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Shover's study also showed that cocaine was predominantly used with fentanyl in the Northeast, while methamphetamine was more commonly concurrently used in the rest of the country.  

That's probably due to "the combination of very low-cost, high-purity methamphetamine outcompeting cocaine and other stimulants at the national level, in addition to an enduring, well-entrenched illicit cocaine market in the Northeast and other pockets of the country," according to the study.

Shover's research analyzes data up to 2021, but some addiction specialists are already anticipating the fifth wave of the overdose crisis based on what they've seen since then. Murray, in Massachusetts, is particularly concerned about the concurrent use of xylazine with opioids. Xylazine, a veterinary tranquilizer, is used to prolong the effects of the high produced by opioids and is of growing concern to harm reduction groups across the country because it's thought that its effects cannot be reversed with naloxone, though a preprint study released this week hints it could.

Ciccarone said he might classify concurrent xylazine use under the fourth wave of multi-substance use, along with stimulants. He is also concerned that counterfeit pills will or are already contributing to the next big wave of overdose deaths.

"The next couple years it's going to be a lot about xylazine and a lot about counterfeit pills, I think," Ciccarone said. "Whether we call that a fifth wave or we give up the notion of waves, I'm not quite sure."

There are things that can be done to reduce overdose deaths. Contingency management has been shown to be effective in treating stimulant use disorder, and buprenorphine can successfully treat opioid use disorder. Naloxone can reverse an overdose and reduce the number of fatal overdoses. And test strips can alert people using drugs to the presence of any potentially fatal contaminants. 

But Murray said many of these solutions are just Band-Aids that, while vitally important to save individual lives, will not work on the scale necessary to abate the crisis. Yet large-scale policies that have been designed to reduce overdose deaths haven't been successful, either. Instead, with every new wave of the overdose crisis, avoiding additional deaths becomes increasingly complex. 

"I feel really good about the lives that we've saved," Murray said. "But I am also very frustrated on a larger scale by our lack of ability to have meaningful solutions."